The present invention relates to a method for preparing serinol which is used as an intermediate in preparing a medical intermediate. More particularly, the present invention relates to a method for preparing serinol (2-amino-1,3-propanediol) of a high purity at high yield by reacting nitromethane with para-formaldehyde and then with sodium hydroxide as a sodium source to give 2-nitro-1,3-propanediol sodium salt and hydrogenating the sodium salt as in the following reaction in the presence of a metal or a metal-impregnated catalyst system. 
Serinol (2-amino-1,3-propanediol) is an intermediate for a medicine and in particular, is used as an intermediate useful for preparing lopamidol, an X-ray contrast medium.
As described, in detail, in U.S. Pat. No. 4,754,079, 2-nitro-1,3-propanediol sodium salt, which is used as a raw material for serinol, can be prepared from nitromethane, paraformaldehyde, sodium methoxide and potassium hydroxide (KOH). The described preparation process in which KOH is used as a catalyst and sodium methoxide in a liquid phase (30% methanol solution) is utilized as a sodium source for 2-nitro-1,3-propanediol sodium salt, is disadvantageous in that the reaction is too complicated and the handling of the compounds is troublesome. In addition, the reaction between para-formaldehyyde and nitromethane must be carried out in a temperature range of 42 to 45xc2x0 C. which is too narrow to control. Further, this process suffers from a problem of being economically unfavorable because sodium methoxide in a aligned phase is expensive compared with sodium hydroxide (NaOH) powder which is used in the present invention.
Another serinol preparation method can be referred to DE Pat. No. 2,742,981, in which 2-nitro-1,3-propanediol sodium salt is hydrogenated in a buffer acid to prepare serinol. In this method, hydrogen is absorbed in a stoichiometric amount, but the yield is merely 30 to 50% even under an ideal reaction condition. Another disadvantage of this method is that it is difficult to apply for industrial production because a Pd/C catalyst is hardly reusable.
According to U.S. Pat. No. 4,448,999, the production yield of serinol may be increased up to 74% by adopting a loop-type reactor equipped with effective cooling means and using methanol as a solvent. However, the batch reaction using a Pd/C catalyst, which is expensive and difficult to reuse, deters users from applying the method for industrial production. In addition, the catalyst must be removed vexatiously with a filter after reaction and the production yield is too low for industrial application.
U.S. Pat. No. 4,221,740 discloses the use of a Raney nickel instead of expensive Pd/C catalyst, asserting that the production yield of serinol can be increased to 64 to 87%. However, the Raney nickel catalyst is also not easy to reuse and requires a filter for its removal. In fact, the production yield is not sufficient.
Therefore, there remains a need for developing a preparation method for serinol which can be conducted even at relatively low temperatures, is economically favorable, and affords a high purity of serinol at a high production yield.
Accordingly, after intensive and thorough research the present inventors found that in the preparation of a 2-nitro-1,3-propanediol salt the use of sodium hydroxide (NaOH) powder as a sodium source unlike the conventional methods and the adoption of a fixed bed reactor system loaded with metals or a metal impregnated catalyst instead of using a conventional batch reactor can prevent the decrease in yield resulting from a reaction temperature rise and overcome the problems of heating para-formaldehyde for a complete dissolution. Based on these findings, the present invention, which is simple and economically favorable and can produce serinol with a purity at a high yield, became complete.
Therefore, it is an object of the present invention to provide a method for preparing serinol with a high purity at a high yield, which is simple and economically favorable.
In one embodiment of the present invention, there is provided a method for preparing serinol (2-amino-1,3-propanediol), comprising the steps of: reacting 1 equivalent of nitromethane with 1 to 10 equivalents of para-formaldehyde and then, adding 0.5 to 5 equivalents of sodium hydroxide to give 2-nitro-1,3-propanediol sodium salt; preparing a catalyst which comprises an inorganic support in which a catalytically effective metal component is impregnated at an amount of 1 to 20 wt %, said catalytically effective metal being selected from the group consisting of palladium (Pd), platinum (Pt), rhodium (Rh), iridium (Ir). ruthenium (Ru), osmium (Os) and mixtures thereof; and continuously hydrogenating the 2-nitro-1,3-propanediol sodium salt in a fixed bed reactor in which the catalyst is packed.
In one version of the embodiment, the present invention comprises of the reaction for preparing the 2-nitro-1,3-propanediol sodium salt at a temperature of 0 to 100xc2x0 C. and the hydrogenation for preparing the 2-nitro-1,3-propanediol at a temperature of 0 to 150xc2x0 C., a hydrogen pressure of 15 to 2,500 psig, and at a weight hourly space velocity (WHSV) of 0.1 to 10 hxe2x88x921 while feeding hydrogen/2-nitro-1,3-propanediol sodium salt at a molar ratio of 1 to 10 with a 1 to 50 wt % solution of 2-nitro-1,3-propanediol sodium salt in a solvent.
In the present invention, nitromethane is first reacted with para-formaldehyde and the resulting compound is salted with sodium hydroxide under absence of catalysts to afford 2-nitro-1,3-propanediol sodium salt which is then allowed to undergo continuous hydrogenation when passing through a fixed bed reactor in which a catalyst comprising a metal or a metal-impregnated support is packed.
Different from conventional ones, the process for the preparation of 2-nitro-1,3-propanediol sodium salt in accordance with the present invention can be readily conducted even at relatively low temperatures. In addition, sodium hydroxide powder, which is used in the present invention, is relatively convenient to handle compared with the aqueous potassium hydroxide solution and sodium methoxide of liquid phase (30% methanol solution), which are conventionally used. In addition, the relatively cheap sodium hydroxide gives an economical advantage to the present invention.
For the preparation of the sodium salt, the amount of para-formaldehyde used preferably ranges from 1 to 10 equivalents per equivalent of nitromethane and more preferably from 1 to 5 equivalents. When the amount of para-formaldehyde is below 1 equivalent, the yield of the sodium salt is poor. On the other hand, when it is over 10 equivalents, side reactions occur.
As for sodium hydroxide, it is preferably used at an amount of 0.5 to 5 equivalents per equivalent of nitromethane and more preferably at an amount of 0.5 to 3 equivalents. Less than 0.5 equivalents of sodium hydroxide slows the reaction rate. On the other hand, greater than 5 equivalents of sodium hydroxide causes side reactions and an economical disadvantage.
The reaction temperature is set in the range of 0 to 100xc2x0 C. and preferably 10 to 50xc2x0 C. For instance, when the reaction is conducted at less than 0xc2x0 C., the formation of the sodium salt is slow. On the other hand, when the reaction temperature exceeds 100xc2x0 C., side reactions frequently occur to reduce the yield of the sodium salt yielding a colored mixture.
In accordance with the present invention, 2-nitro-1,3-propanediol sodium salt can be produced with a purity of 99.8% at a yield of 98%.
Subsequently, the 2-nitro-1,3-propanediol sodium salt is hydrogenated in the presence of a metal catalyst or a catalyst system comprising a metal-impregnated support, so as to produce serinol of a high purity at a high yield. This hydrogenation is accomplished in a continuous process using a fixed bed reactor. Therefore, the method of the present invention has an advantage over other processes using batch type processes, in production rate. In addition, the method of the present invention is economically favorable by virtue of the regeneration of the catalyst and not vexatious but simple because the catalyst needs not be removed by a filter system.
For the hydrogenation of 2-nitro-1,3-propanediol sodium salt into serinol, a suitable solvent should be used. This solvent is required to dissolve a solid salt of 2-nitro-1,3-propanediol sodium salt so sufficiently as to achieve the smooth feeding of the reactant into the reactor in addition to absorbing the reaction heat generated during the hydrogenation, an exothermic reaction, and not to react with the reactants, 2-nitro-1,3-propanediol sodium salt and hydrogen. Suitable for the hydrogenation of the present invention is one selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, water and mixtures thereof with preference to a mixture of methyl alcohol and water. A mixture of 9:1 methyl alcohol:water is most preferable. In the solvent, 2-nitro-1,3-propanediol sodium salt is maintained at a concentration of 1 to 50 wt % and preferably 3 to 20 wt %. Further, the solvent can be heated to dissolve fully if required. If 2-nitro-1,3-propanediol sodium salt below 1 wt % is used, serinol is obtained at a poor yield. On the other hand, a content of greater than 50 wt % brings about a reduction in selectivity and conversion rate.
The hydrogenation of 2-nitro-1,3-propanediol sodium salt is carried out in the presence of a catalyst. This catalyst is either a metal itself or a metal impregnated in a support. The catalytically effective metal component is selected from the group consisting of nickel (Ni), palladium (Pd), platinum (Pt), rhodium (Rh), iridium (Ir), ruthenium (Ru), osmium (Os), and mixtures thereof with preference to palladium or ruthenium. As the support useful in the present invention, an inorganic oxide may be used. Examples of the inorganic oxide include alumina, silica, silica-alumina, zirconia, titania, zeolite and molecular sieves with most preference to alumina.
The support particles may be in a form of a sphere, a cylinder, a granule or any shape. However, they are preferably formed into spherical or cylindrical pellets for suitable mechanical properties.
When being impregnated in a support, the catalytically effective metal component is used at an amount of 1 to 20 wt % based on the weight of the total catalyst system and more preferably at an amount of 1 to 15 wt %. For instance, when the content of metal is below 1 wt %, the hydrogenation occurs slowly. On the other hand, when the content of metal is over 20 wt %, the expensive precious metal increases the production cost. When palladium or ruthenium is used as a catalytically effective metal component, the preferable content thereof is 5 to 20 wt % based on the total catalyst system.
Impregnation of the metal in the support may be carried out using an incipient wetness impregnation method, an excess water impregnation method, a spray method, or a physical mixing method.
After completion of the metal impregnation, the catalyst should be calcined for 2 hours or more in an air or an inert gas atmosphere. The calcination temperature ranges from 300 to 700xc2x0 C. and preferably from 300 to 550xc2x0 C. At a calcination temperature of less than 300xc2x0 C., the metal precursor impregnated in the support is insufficiently decomposed. On the other hand, a calcination temperature of greater than 700xc2x0 C. lowers the dispersion of the metal, resulting in a poor performance of the catalyst.
After being packed in a fixed bed reactor, the calcined catalyst is allowed to undergo the reduction with hydrogen prior to feeding the reactant into the reactor. This reduction condition should be maintained for at least 2 hours at 50 to 400xc2x0 C. depending on the metals used.
A feature of the present invention resides in that a fixed bed reaction system is employed in which the catalyst is packed. The fixed bed reactor system guarantees higher space time yields, allows the catalyst to be reused, and makes the process simple. In the fixed bed reaction system, no limitations are imposed on the configuration of the reactor and the feeding type and flow direction of the reactant. In order to render the reactants to be brought into good contact with each other, however, there is preferably used a trickle-bed reactor in which the reactants hydrocarbons and hydrogen flow downwardly while being dispersed uniformly.
The preparation of serinol, resulting from the hydrogenation of 2-nitro-1,3-propanediol sodium salt, can be achieved under the condition of a hydrogen pressure of 15 to 2,500 psig, a reaction temperature of 0 to 150xc2x0 C., and a weight hourly space velocity (WHSV) of 0.1 to 10 hxe2x88x921, preferably under the condition of a hydrogen pressure of 100 to 2,000 psig, a reaction temperature of 10 to 100xc2x0 C., and a WHSV of 0.2 to 10 hxe2x88x921, and most preferably under the condition of a hydrogen pressure of 500 to 1,500 psig, a reaction temperature of 20 to 80xc2x0 C., and a WHSV of 0.5 to 5 hxe2x88x921. A change in WHSV has a significant influence on the hydrogenation selectivity for serinol as shown in FIG. 1 in which the hydrogenation selectivities for serinol according to catalysts are plotted vs. WHSV. In addition, as will be elucidated later, the conversion and the selectivity in the hydrogenation of 2-nitro-1,3-propanediol sodium salt both increase with a particular amount of the catalyst used, but no more increase is obtained when the catalyst is used at an amount greater than the critical value, as shown in Table 2, below. Therefore, when the reaction condition is deviated from the above ranges, a decrease is found in the yield of serinol while an increase in the deactivation rate of the catalyst. Under such a deviated condition, advantage cannot be taken of the continuous process suggested by the present invention.
3.5 moles of hydrogen is sufficient to accomplish the complete conversion of 1 mole of 2-nitro-1,3-propanediol sodium salt by hydrogenation. The amount of the hydrogen fed is not limited if it is greater than 3.5 moles per mole of 2-nitro-1,3-propanediol, but the molar ratio of hydrogen to 2-nitro-1,3-propanediol is preferably determined in the range of 1-10 because of process economy. The hydrogen which is not reacted, but passes the reactor may be re-compressed and recycled to the reactor.
The reaction products effluent from the reactor are directed to a solvent-recovery unit in which at least a portion of the solvent used is separated from the other effluent components. This recovery unit may be one of any type, such as a distillation tower or a flash vaporizer. The products or concentrates effluent from a lower part of the solvent-recovery unit are transferred to a vacuum distillation apparatus.